BANGKOK, THAILAND – 21 Oct, 2017 – The University of Miami Miller School of Medicine, through its various departments, has conducted a phase II, randomised, double-blind, placebo-controlled clinical trial of allogeneic mesenchymal stem cells, and their role and effects in improving aging frailty. The study is known as the CRATUS trial.
Frailty, is increasingly becoming a common syndrome in older adults. It is a geriatric syndrome often characterised by weakness, weight loss and low activity that is associated with adverse health outcomes.
However, frailty should not be confused for normal, chronological aging. The frailty syndrome is mostly driven by biological aging processes that include inflammation and stem cell dysfunction; whereas chronological aging is the number of years one has lived and which inevitably results in one naturally becoming older.
There are two main models that are used to define frailty. These are:
- The deficit model – this model accounts for a person’s geriatric syndromes, diseases, physical, psychosocial, and cognitive impairments. These factors also form what is known as a “Frailty Index.”
- The phenotype model – the physical phenotype model is comprised of at least three factors that could include: weight loss, exhaustion, weakness, slowness and decreased physical activity. Together, these form an underlying system of multisystem dysregulation.
Currently, the only mechanisms used to tackle frailty include: physical exercise, caloric support, vitamin D and optimization of polypharmacy. However, there are, unfortunately, no current interventions that are able to reverse or ameliorate frailty.
It is with this regard, that the placebo-controlled clinical trial was conducted. Phase I of the study was an open-label study of human allogeneic mesenchymal stem cells (allo-hMSCs) intravenously infused for frailty. The study showed that the allo-hMSCs could be safely administered, they reduced inflammation and improved measures of functional capacity.
The current phase II, double-blinded, placebo-controlled study was then conducted. It aims to test the hypothesis that exogenous allo-hMSCs could reverse signs and symptoms of frailty in older persons.
CRITERIA
For the phase II study, patients:
– were provided written informed consent
– were aged between 60 and 95 years old at the time of signing the consent form
– showed signs of frailty based on a physician assessment
STUDY END POINTS
The primary end points of the study was the safety of allo-hMSCs at one month. This was assessed by treatment emergent-serious adverse events (TE-SAE) which were defined by: stroke, nonfatal pulmonary embolism, death, worsening dyspnea and clinically significant laboratory abnormalities.
The secondary end points mainly evaluated the efficacy of the therapy. This was measured by the rate of change in frailty markers as defined by: reduced activity, slowing of mobility, 4-m gait speed test and the short physical performance battery score (SPPB).
RESULTS
Of the patients that participated in the clinical trial, 60% of them were male, and the average age was 75.5.
Safety – In regards to safety, no TE-SAE occurred in any of the patients in the first 30 days. None of the patients showed any signs of adverse cardio-pulmonary reaction after the intravenous infusion. Also, there were no cumulative, treatment-related SAEs in experienced by the patients throughout the duration of the study. Additionally, there were no clinically significant changes in basic hematologic and chemistry laboratory tests throughout the duration of the study.
Hospitalisation – There were four patients who required hospitalization within the 12-month follow-up. Two of the hospitalizations were reported in one patient in the 100M-group, both of which were moderate in severity; however, none of the hospitalizations were secondary to the procedure. No patients in the 200M-group were hospitalized. The remaining three patients belonged to the placebo group; one patient had two moderate hospitalizations and one severe, another had a hospitalization that was moderate in severity, and another had one severe hospitalization. None of the hospitalizations were related to the procedure.
Long-term Adverse Events – One patient in the 200M-group died of an unrelated event prior to the 12-month follow-up. Additionally, one patient in the placebo had an unrelated stroke 307 days postinfusion. The proportion of patients with adverse events at 12 months did not differ between groups at the 6 – and 12-month time points (p = .300 and p = .141, respectively).
Quality Of life – Quality of life and functional status were monitored throughout the study. These outcomes preferentially improved in patients randomized to receive 100M allo-hMSCs. The 6MWT increased in the 100M-group from baseline to 6 months.
Sexual Quality Of Life – In female patients, their sexual quality of life, (SQOL-F) showed a remarkable increase in the 100M-group at 6 months. However, there were no changes shown in the 200M or placebo groups. Conversely, there were no changes among male participants in the IIEF from baseline to 6 months.
CONCLUSION
The CRATUS trial is a randomized, double-blind, placebo-controlled evaluation of allo-hMSCs to treat the signs and symptoms of frailty. The aforementioned results support the safety and feasibility of administering allo-hMSCs in this population.
With regard to efficacy, there was a preferential effect towards improvement of functional capacity and patient reported outcome measures in patients receiving lower dose MSCs, although immunologic bioactivity was evident with both doses. Together, these findings suggest that allo-hMSCs may be an effective biological modifier of aging frailty, and support ongoing investigation of allo-hMSCs alone or as an adjunct to current physical training strategies for aging frailty.
These findings are in agreement with a recently completed dose-finding phase I safety study. In that study, two important sets of observations were made. First, a constellation of physical performance measures improved with cell therapy, and second, 100M cells represented the peak responsiveness dose, with a plateau and/or reduction in efficacy being noted with 200M cells. Accordingly, this study was based, in part, on phase I. Importantly, randomizing patients in a double-blind fashion to 100M cells, 200M cells, or placebo was performed to validate the results of the earlier study and to confirm both the constellation of physical performance findings and the dose–response.
There are several factors that could contribute to nonlinear dose response curves with cell-based therapy. These include variation in functional activity of the cells rather than the absolute number of cells infused. In this regard, higher cell concentrations could impair cell activity through physical effects such as concentration-dependent cell aggregation, or damage of cells due to excessive shear forces on cells during infusion that could influence the relationship between cell dose and clinical benefit.
However, as with all progenitor cell types in various disease processes, whether modified or not, exact dosing has yet to be established. Given the novel use of MSCs in frailty, a patient population for whom a successful therapy has yet to be developed, dosing was based on safety as established by previous studies and phase I, and was further investigated in the current study. Importantly, safety was ultimately established in both cell-dose groups. The optimal effective dosing will be investigated in future larger randomized trials.
For more information on the CRATUS trial or on how stem cells can be used for yourself or a loved one, please contact us. One of our highly skilled stem cell representatives will be able to assist you at your earliest convenience.
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